N-terminal modifications as fate switches in neurodegeneration: a mechanistic review.

The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer's, Parkinson's, and Huntington's diseases by regulating the protein lifespan, folding, and interaction with protein/DNA. In particular, Nt acetylation shields proteins from degradation or targets them for the same, thereby affecting their fate. Distinct enzymes catalyze Nt acetylation, Nt methylation, and Nt myristoylation, and these modifications compete for the nascent polypeptide at the ribosomal exit tunnel. Dysregulation of Nt modifications initiates the protein aggregation cascade and could potentially induce neuroinflammation and neurodegeneration. Here, we review Nt modifications and their emerging roles in the pathogenesis of NDs. Further, we highlight the crosstalk among distinct Nt modifications and explore how their convergence may shape disease vulnerability and progression.